Osteopontin protects against lung injury caused by extracellular histones

Abstract

Extracellular histones are present in the airways because of cell death occurring during inflammation. They promote inflammation and cause tissue damage due to their cationic nature. The anionic phosphoglycoprotein osteopontin (OPN) is expressed at high levels during airway inflammation and has been ascribed both pro- and anti-inflammatory roles. In this study, it was hypothesized that OPN may neutralize the harmful activities of extracellular histones at the airway mucosal surface. In a model of histone-induced acute lung injury, OPN mice showed increased inflammation and tissue injury, and succumbed within 24 h, whereas wild-type mice showed lower degrees of inflammation and no mortality. In lipopolysaccharide-induced acute lung injury, wild-type mice showed less inflammation and tissue injury than OPN mice. In bronchoalveolar lavage fluid from ARDS patients, high levels of OPN and also histone-OPN complexes were detected. In addition, OPN bound to histones with high affinity in vitro, resulting in less cytotoxicity and reduced formation of tissue-damaging neutrophil extracellular traps (NETs). The interaction between OPN and histones was dependent on posttranslational modification of OPN, i.e., phosphorylation. The findings demonstrate a novel role for OPN, modulating the pro-inflammatory and cytotoxic properties of free histones.

Bioinformatics analysis of the potential biomarkers for acute respiratory distress syndrome

“…However, in a different study, OPN was found to be beneficial [27]. Recent research suggested that OPN reduced histone-induced lung injury via binding to histones [28]. Although OPN exhibits both pro-inflammatory and anti-inflammatory effects, inflammatory mediators and OPN comprise a complex network, leading to uncontrolled inflammation in the lungs during the occurrence and development of ARDS.…”

Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight

“…However, intracellular OPN (iOPN) is also expressed [5,37,38] from an alternative downstream transcription initiation site that results in skipping of the first 16 amino acids that function as a membrane localization signal peptide [5,39]. In the lungs, OPN is observed in the sputum (average level of 53 pg/mL) [40] and bronchoalveolar lavage fluid (BALF; average level of 1.1 ng/mL) [41] of healthy individuals, constitutively secreted by airway epithelial cells and alveolar macrophages and exerting diverse functions dependent on its phosphorylation status [42]. In general, sOPN presents different and specific patterns of post-translational modifications according to its cell of origin.…”

“…In more detail, during NETosis, neutrophil DNA traps pathogens, thereby also releasing cytotoxic cationic histones. OPN with its anionic structure can bind these histones and limit their toxic effects [42].…”

Extracellular histones in lung dysfunction: a new biomarker and therapeutic target?

“…The formation of PTX3-NET complexes in sepsis patients and the improved survival of PTX3 overexpressing mice from LPS or CLPinduced sepsis underscores the importance of this molecule against histone-induced diseases [42][43][44] . Recently, an anionic phosphoglycoprotein, osteopontin has been shown to strongly bind to histones and attenuate their cytotoxicity 45 . Higher levels of osteopontin had been detected in BAL from ARDS patients, likely as a self-protecting response.…”